A Study to Evaluate the Tolerability of Botox and Topiramate or Botox and Placebo and Effect on Cognitive Efficiency

A Randomized, Pilot Study to Evaluate the Tolerability of OnabotulinumtoxinA Plus Topiramate vs. OnabotulinumtoxinA Plus Placebo and Long Term Effect of Treatment on Cognitive Efficiency and Continuation of Care

The purpose of this study is to evaluate sustained tolerability, quality of life, and change in cognitive efficiency following treatment with OnabotulinumtoxinA and daily topiramate vs. OnabotulinumtoxinA and daily placebo (Group A vs. Group B).

Numerous migraine preventive medications are well known to be associated with cognitive impairment and disruption of mood.

Clinvest would propose a pilot study of chronic migraine patients randomized 1:1 to onabotulinumtoxinA and daily topiramate or onabotulinumtoxinA and placebo. This pilot study will examine the degree to which subjects are able to tolerate and are satisfied with a migraine preventive medication in addition to onabotulinumtoxinA over an extended period of time and the effect of the subjects' quality of life compared with onabotulinumtoxinA as a single therapy. It will also assess short and long term effects of these two treatments on cognition. Cognitive performance will be measured by the Mental Efficiency Workload Test (MEWT), a repeated measures handheld neuropsychological test battery that measures mental efficiency via 4 sub-tests (Simple Reaction Time, Running Memory, Continuous Performance Task, Matching to Sample, and Mathematical Processing) to demonstrate short and long term changes in mental status compared to their baseline. The Controlled Oral Word Association Test (COWAT) will be used to test verbal fluency and screen for anomic aphasia, a known side effect of several migraine prophylactic medications including topiramate.

Visit 1 - Screening / Baseline Following Informed Consent a medical, headache, and medication history will be collected and a physical and neurological exam performed on all subjects. A urine pregnancy test will be collected from any subject of child-bearing potential. Vital signs and ECG (at the discretion of the investigator) will be completed. The Mental Efficiency Workload Test (MEWT) will be administered 3 times to establish a cognitive efficiency baseline. The COWAT will be completed. Subjects will be instructed regarding completion of the online 1-month Baseline Period Migraine Diary and be instructed to treat headaches during the 1-month Baseline Period with their usual acute migraine medication in their usual manner.

Visit 2 - Randomization / Injection Following the 1-month Baseline Period, any change in medical or medication history since the previous visit will be collected and a pregnancy test collected if appropriate. Vital signs will be recorded. Subjects continuing to meet eligibility criteria will be instructed to complete the online Treatment Period Migraine Diary daily. The MEWT, HIT-6, Migraine Specific Questionnaire (MSQ) and COWAT will be completed. The coordinator will assess compliance with online headache diary and any deviation outside of 100% compliance should be documented at the site. If in the investigator's opinion, the subject maintained a high level of compliance with the online headache diary, subjects will then be randomized into the study.

Eligible subjects will be randomized 1:1 in a blinded fashion to receive onabotulinumtoxinA at 31 fixed-site, fixed-dose injections across seven (7) specific head/neck muscle areas and daily topiramate (Group A) or onabotulinumtoxinA at 31 fixed-site, fixed-dose injections across seven (7) specific head/neck muscle areas and placebo to match topiramate (Group B).

Daily study medication (topiramate or placebo) will be dispensed for the following 3 months.

The Group A topiramate titration schedule will be as follows:

Week 1: topiramate 25 mg qhs (every night at bedtime) Week 2: topiramate 25 mg bid (twice a day) Week 3: topiramate 25 mg q am (everyday before noon) + topiramate 50 mg qhs Week 4: topiramate 50mg bid

Only one dosage adjustment (increase or decrease), based on efficacy or tolerability, may be made at the investigator's discretion. Subjects must maintain a dose of at least 50 mg/day to remain in the Treatment Period.

The Group B placebo schedule will be as following:

Week 1: 1 tab qhs Week 2: 1 tab bid Week 3: 1 tab q am + 2 tabs qhs Week 4: 2 tabs bid

Subjects will be instructed to complete the online daily Treatment Period Migraine Diary during the next 3-month period.

Following Visit 2, subjects will be phoned monthly and any adverse events collected. Subjects will also be sent weekly reminders for 8 weeks following Visit 2 via email to take study medication, complete online diary and contact their coordinator for any questions or concerns they may have. During the titration period, any subject in Group A experiencing an adverse event thought to be related to study medication dosage will return to the clinic at an Unscheduled Visit for dosage adjustment.

Visit 3

Three months following Visit 2, subjects will return and complete the MEWT, HIT-6, MSQ, COWAT, and Subject's Global Impression of Change (SGIC). The Investigator will complete a Physician's Global Impression of Change (PGIC). Any change in medical or medication history since the previous visit will be collected and a pregnancy test collected if appropriate. Vital signs will be recorded. The coordinator will assess compliance with online headache diary and any deviation outside of 100% compliance should be documented at the site. If in the investigator's opinion, the subject maintained a high level of compliance with the online headache diary, subjects will be allowed to continue in the study.

All subjects will be administered a dose of 155 U onabotulinumtoxinA at 31 fixed-site, fixed-dose injections across seven (7) specific head/neck muscle areas.

Any unused study medication and used packaging will be collected, drug accountability will be performed, and daily study medication (topiramate or placebo) will be dispensed for the following 3 months.

Subjects will be instructed to complete the online daily Treatment Period Migraine Diary during the next 3-month period.

Following Visit 3, subjects will be phoned monthly and any adverse events collected.

Visit 4

Three months following Visit 3, subjects will return and complete the MEWT, HIT-6, MSQ, COWAT, and Subject's Global Impression of Change (SGIC). The Investigator will complete a Physician's Global Impression of Change (PGIC). Any change in medical or medication history since the previous visit will be collected and a pregnancy test collected if appropriate. Vital signs will be recorded. The coordinator will assess compliance with online headache diary and any deviation outside of 100% compliance should be documented at the site.

All subjects will be administered a dose of 155 U onabotulinumtoxinA at 31 fixed-site, fixed-dose injections across seven (7) specific head/neck muscle areas.

Any unused study medication and used packaging will be collected, drug accountability will be performed, and daily study medication (topiramate or placebo) will be dispensed for the following 3 months.

Subjects will be instructed to complete the online daily Treatment Period Migraine Diary during the next 3-month period.

Following Visit 4, subjects will be phoned monthly and any adverse events collected.

Visit 5

Three months following Visit 4, subjects will return and complete the MEWT, HIT-6, MSQ, COWAT, and Subject's Global Impression of Change (SGIC). The Investigator will complete a Physician's Global Impression of Change (PGIC). Any change in medical or medication history since the previous visit will be collected and a pregnancy test collected if appropriate. Vital signs will be recorded. The coordinator will assess compliance with online headache diary and any deviation outside of 100% compliance should be documented at the site.

All subjects will be administered a dose of 155 U onabotulinumtoxinA at 31 fixed-site, fixed-dose injections across seven (7) specific head/neck muscle areas.

Any unused study medication and used packaging will be collected, drug accountability will be performed, and daily study medication (topiramate or placebo) will be dispensed for the following 3 months.

Subjects will be instructed to complete the online daily Treatment Period Migraine Diary during the next 3-month period.

Following Visit 5, subjects will be phoned monthly and any adverse events collected.

Visit 6

Three months following Visit 5, subjects will return and complete the MEWT, HIT-6, MSQ, COWAT, and Subject's Global Impression of Change. The Investigator will complete a Physician's Global Impression of Change. Any change in medical or medication history since the previous visit will be collected and a pregnancy test collected if appropriate. Vital signs will be recorded. The coordinator will assess compliance with online headache diary and any deviation outside of 100% compliance should be documented at the site.

Any unused study medication and used packaging will be collected and drug accountability will be performed.

Subjects will exit the study at Visit 6.

Inclusion Criteria:

1. must be outpatient, male or female, of any race, between 18 and 65 years of age.

2. if female of child bearing potential must have a negative pregnancy test result at the Screening Visit and practice a reliable method of contraception.

   A female is considered of childbearing potential unless she is post-menopausal for at least 12 months prior to administration of study drug, without a uterus and/or both ovaries or has been surgically sterilized for at least 6 months prior to study drug administration.

   Reliable methods of contraception are:

   Complete abstinence from intercourse from 2 weeks prior to administration of the investigational product. Throughout the study, and for a time interval (5 days) after completion or premature discontinuation from the study. History of bilateral tubal ligation Sterilization of male partner; or, Implants of levonorgestrel; or, Injectable progestogen, or, Oral contraceptive (combination therapy with ethinyl estradiol plus a progestin) with a placebo week every 1-3 months; or, Any intrauterine device (IUD) with published data showing that the highest expected failure rate is less than 1% per year (not all IUD's meet this criterion) in use at least 30 days prior to study drug administration; or, Spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a female diaphragm); or, Any other barrier methods (only is used in combination with any of the above acceptable methods) in use at least 14 days prior to study drug administration; or, Any other methods with published data showing that the highest expected failure rate for that method is less than 1% per year.

3. must have history of chronic migraine (with or without aura) according to the criteria proposed by the Headache Classification Committee of the International Headache Society (IHS) for at least 3 months prior to enrollment.

4. must be able to understand the requirements of the study including maintaining a headache Diary, and signing informed consent.

5. must be in good general health as determined by investigator.

6. if taking migraine preventive, must be on a stable dose of preventive medication for at least 6 weeks prior to screening.

7. must have daily access to internet for completion of online daily headache diary.

Exclusion Criteria:

1. if female, is pregnant, planning to become pregnant during the study period, are breast feeding, or are of childbearing potential and not practicing a reliable form of birth control.
2. has headache disorders outside IHS-defined chronic migraine definition.
3. has evidence of underlying pathology contributing to their headaches.
4. has any medical condition that may increase their risk with exposure to OnabotulinumtoxinA including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any other significant disease that might interfere with neuromuscular function.
5. has profound atrophy or weakness of muscles in the target areas of injection.
6. has skin conditions or infections at any injection site.
7. has allergy or sensitivities to any component of the test medication.
8. has previously received onabotulinumtoxinA for migraine prevention.
9. has previously received topiramate.
10. who in the opinion of the investigator, has active major psychiatric or depressive disorders including alcohol/drug abuse.
11. meets International Headache Society criteria for Medication Overuse Headache with opioid or butalbital containing products.
12. who in the opinion of the investigator, is taking opioid or butalbital containing products more than once a week that could be contributing to a pattern of increased headaches or cognitive decline.
13. is planning or requiring surgery during the study.
14. has a history of poor compliance with medical treatment.
15. is currently participating in an investigational drug study or has participated in an investigational drug study within the previous 30 days of the screening visit.